Dose dependent pharmacokinetics of theophylline: Michaelis-Menten parameters for its major metabolic pathways

Abstract

Dose Dependency for pharmacokinetics of theophylline and the formation of its major metabolites, 3-methylxanthine (3-MX); 1-methyluric acid (1-MU); 1,3-dimethyluric acid (DMU), were examined by administering three single oral doses (250, 375, 500 mg) of theophylline to six healthy adult volunteers. The serum and urine concentrations of theophylline and the metabolites in serum and urine were determined by high-performance liquid chromatography. Total clearance of theophylline decreased and its half life increased over the range of doses administered (p<0.01). There was a significant dose related decrease in the fractional recovery of 3-MX and 1-MU (p<0.001) and a dose related increase in fractional excretion of DMU and unchanged theophylline (p<0.01 and p<0.001 respectively). No significant dose related changes were observed in the renal clearance of 3-MX, 1-MU and DMU, indicating linear urinary excretion kinetics of the metabolites. Theophylline metabolic clearance to 3-MX as well as to 1-MU decreased with increasing dose but clearance to DMU remained unnaffected by the size of dose. The individual Michaelis-Menten parameters Km and Vmax were estimated for six subjects receiving three different single doses. The Km values for theophylline metabolism to 3-MX, 1-MU and DMU were 2.4+/-0.6, 5.1+/-1.8+/- and 112.3+/-36.8 mg/L respectively and the Vmax values were 3.5+/-0.7, 7.5+/-2.6 and 112.3+/-36.8 mg/hr respectively. The Km values for the N-demethylation pathways (3MX and 1-MU) were lower corresponding to therapeutic serum concentrations of drug. These results suggest that the elimination kinetics of theophylline is nonlinear in the human in the therapeutic range of serum concenntrations and can be explained by saturable formation kinetics of 3-MX and 1-MU. In contrast to previous studies we didn't find obvious indication for nonlinear formation of DMU at therapeutic concentration range.